INHIBIDORES DE BRAF Y MEK DIRIGIDA CON TERAPIA · INHIBIDORES DE BRAF Y MEK ... Supervivencia con inhibición BRAF/MEK en función de inhibidor ... Los inhibidores kinasa pueden rescatar

TERAPIA DIRIGIDA CON INHIBIDORES DE BRAF Y MEK

Beatriz Nieto Mangudo

Unidad de Melanoma CAULE

El melanoma es una neoplasia conducida por la vía MAPK

NRAS

BRAF

Erk

MEK

SurvivalProliferation

KIT

La inhibición de RAF depende del estatus de BRAF

Adapted from Poulikakos PI, et al. Cancer Cell. 2011;19:11-15.

Wild-type BRAF (all other cells)Mutated BRAF V600 (tumor cells)

MutBRAF

MEK

Constitutively active High MEK activity

MutBRAF

DRUG

RAF inhibitor suppresses MEK activity

MEK

RAF RAF RAF RAFActive RAS DRUG DRUGDRUG ATP

All sites inhibitor-bound MEK activity inhibited

RAF Dimers = inhibitor–induced MEK activity

RAF

DRUG

MEK MEK MEK

RAF Dimers = Elevated MEK activity

RAF Monomers =Low MEK activity

Active RAS

RAF RAF RAF

MEK MEK

Without RAF Inhibitor

With RAF Inhibitor

Inhibidores vía MAPK disponibles en Melanoma

■ Inhibidores RAF : vemurafenib[1] y dabrafenib[2]

■ Altas tasas de respuesta■ Mediana de duración de la respuesta: 6-8 meses■ Respuesta en el cerebro[3]

■ Inhibidor MEK : trametinib[4] y Cobimetinib■ Moderada tasa de respuesta (~ 20%) y aumento de supervivencia en

melanoma BRAF-mutado■ No efectivo tras progresión a inhibidor RAF ■ Papel más importante en combinación con inhibición RAF[5]

1. Martin-Liberal J, et al. Future Oncol. 2015;11:579-589. 2. Khoja L, et al. Expert Rev Anticancer Ther. 2015;15:265-276. 3. Harding JJ, et al. Oncologist. 2015;20:789-797. 4. Chopra N, et al. Expert Rev Anticancer Ther. 2015;15:749-760. 5. Long GV, et al. Lancet. 2015;[Epub ahead of print].

Terapias dirigidas en Estadio IV: principales estudios

NRAS

CRAFBRAF

MEK

ERK

BRIM-3:BRAF•Vemurafenib vs DTIC

Melanoma IIIC ó IVBRAF V600E/V600KPrimera líneaPS 0-1Mtx cerebrales controladas 12 semanas tras ttoCrossover permitido

BREAK-3:BRAF•Dabrafenib vs DTIC

OSPFS

BRIM-3 Fase III Vemurafenib vs Dacarbazine en Melanoma: OS

BRAFi en Primera línea: PFS

Vemurafenib vs Dacarbacina Dabrafenib vs DTIC

Lancet Oncol 2014; 15: 323–32 Lancet. 2012 Jul 28;380(9839):358-65.

BRAF i en Primera línea: OS



BRAF i en Primera línea : TR



NRAS

CRAFBRAF

MEK

ERK

BREAK-3:BRAF•Dabrafenib vs DTIC•RR 59%,mPFS 6.9m•HR OS/PFS: 0.77/0.37

BRIM-3:BRAF•Vemurafenib vs DTIC•RR 57%,mPFS 6.9m•HR OS/PFS: 0.7/0.38

Metric: BRAF•Trametinib vs QT


322 pacientesMelanoma avanzadoBRAF V600E/V600K1ª ó 2ª línea no BRAFiObj. Primario: SLPCrossover permitido

METRIC: Fase III Trametinib (MEKi) vs Dacarbazine o Paclitaxel

Flaherty KT, et al. N Engl J Med. 2012;367:107-114.

1.0

0.8

0.6

0.4

0.2

00 2 4 6 8

Mos Since Randomization

Prob

abili

ty o

f PFS

4.8 vs 1.5mesesHR: 0.47 (95% Cl: 0.34-0.65; P < .001)

Trametinib(n = 214)

Chemotherapy(n = 108)

Prob

abili

ty o

f OS

1.0

0.8

0.6

0.4

0.2

00 2 4 6 8 10

Trametinib(n = 214)

Chemotherapy(n = 108)

OS a 6 meses 81 vs 67%HR: 0.54 (95% Cl: 0.32-0.92; P = .01)


Eventos adversos más comunes con las nuevas terapias dirigidas en Melanoma Avanzado

AE (≥ Grade 2), % Vemurafenib[1] Dabrafenib[2] Trametinib[3]

Arthralgia 21 5 NRRash 18 NR 27Fatigue 13 6 9Cutaneous SCC/ keratoacanthoma

12/8 6 (combined) NR

Hyperkeratosis 6 13 NRPyrexia NR 11 NRHeadache 5 5 NRPhotosensitivity (any grade) 12 3 NRHypertension NR NR 12

1. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516. 2. Hauschild A, et al. Lancet. 2012;380:358-365. 3. Flaherty KT, et al N Engl J Med. 2012;367:107-114.

Resistencia a Inhibidores BRAF

Sosman J, et al. N Engl J Med. 2012;366:707-714.

BRIM-2 Fase II Vemurafenib en Melanoma Metastásico : PFS

Indi

vidu

al P

atie

nts

Trea

ted

With

Vem

uraf

enib

TTPTime to responseDiedAlive with response

Mos0 202 4 6 8 10 12 14 16 18

Resistencia a inhibidor BRAF

Intrínsecos

CDK 4cyclin D1 amplificada(CCN1)15-20%melanomasRESISTENCIAa BRAFi

Pérdida PTEN(corta PFS),bcl2a1 amplBraf fusion,GNAQ,RAC1P298,Pérdida NF1 RESISTENCIAa BRAFi

HGF, CMETRESISTENCIAa BRAFi

Adquiridos

No dependientes de ERK(ERK todavíainhibido)

ERK dependiente(ERKreactivado)

Sullivan et al. Eur J Cancer 2013: 1297-1304

Turajlic Annals 2014

Resistencia a inhibidor BRAF

Nazarian R, et al. Nature. 2010;468:973-977. Johannessen CM, et al. Nature. 2010;468:968-972. Villanueva J, et al. Cancer Cell. 2010;18:683-695. Wagle N, et al. J Clin Oncol. 2011;29:3085-3096. Shi H, et al. Nat Commun. 2012;3:724. Poulikakos PI, et al. Nature. 2011;480:387-390. Straussman R, et al. Nature. 2012;487:500-504. Whittaker SR, et al. Cancer Discov. 2013;3: 350-362. Maertens O, et al. Cancer Discov. 2013;3:338-349.

CRAF

BRAF

MEK

ERK

P

P

BRAF

BRAF

BRAF BR

AF

NRAS

COT

MEK

Alternative splicing

Amplification

PI3K

NF1

Espectro de resistencias

Datos de 3 grandes estudios de resistencias

100 pacientes con 132 muestras de resistencias adquiridas

Douglas Jonhson ASCO 2015



Número PorcentajeMutación NRAS 23 17

Mutación KRAS 3 2

Splicing BRAF 21 16 (25)

Amplificación BRAF 17 13

Mutación MEK1/2 9 7

Otras alteraciones MAPK 3 2

Alteraciones no MAPK 14 11

Mecanismo no identificado

55 42


•Las mutaciones NRAS, variantes BRAF y mutaciones MEK1/2 ocurren más a menudo aisladas

•Las amplificaciones BRAF y las alteraciones no ligadas a la vía MAPK concurren con otras alteraciones más de manera más frecuente

•Varias mutaciones son mutuamente excluyentes


Espectro de resistencias: asociaciones clínicas

•PFS fue similar independientemente del mecanismo de progresión

•Diferente patrón de progresión según mecanismo de resistencia:

NRAS más frecuente en cerebro, menos en pulmón

MEK 1/2 más frecuente en hígado


¿Cómo frenar estas resistencias?

MEKi (Trametinib) en Melanoma Metastásico BRAF-Mutado/BRAFi-Nativo

Robert C, et al. ASCO 2012. Abstract LBA8509.

Disease Stage

39%

Trametinib (n = 214)

Confirmed RR: 22% (95% CI: 16.6-28.1)M1cM1bM1aIIIC

Unknown

100

80

60

40

200

-20

-40

-60

-80

-100

% C

hang

e Fr

om B

asel

ine

in

Dia

met

ers

of T

arge

t Les

ions

Inhibidor MEK en monoterapia tiene mínima actividad en pacientes refractarios a BRAFi

Unconfirmed RR: 5% (95% CI: 0.6-16.9) 1 CR, 1 PR, 11 SD

*Discontinued prior BRAFi due to toxicityK = V600K

M1cM1a M1bM Stage at Screening

KK

K

K

*

Max

imum

Red

uctio

n in

Tar

get L

esio

ns

From

Bas

elin

e (%

)

*

*

Kim KB, et al. J Clin Oncol. 2013;31:482-489.

100

80

60

40

20

0

-20

-40

-60

-80

-100

Inhibición combinada BRAF y MEK en Melanoma BRAFV600-Positivo

Flaherty KT, et al. N Engl J Med. 2012;367:1694-1703.

Full-dose BRAF/MEKFull-dose BRAF/half-dose MEKFull-dose BRAF

Full-Dose BRAF/MEK Full-Dose BRAFMedian PFS, mos 9.4 5.8HR 0.39 (P < .001)1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18


Prob

abili

ty o

f PFS

Resistencia retardada con la combinación BRAF/MEK vs monoterapia con BRAFi

Regresión tumoral con la combinación BRAF/MEK en pacientes refractarios a BRAFi

Max

imum

Per

cent

Red

uctio

nFr

om B

asel

ine

Mos Since Prior BRAFi

PRSDPD

Best Response on Prior BRAFiRR: 19%

M = Prior MEKi

Flaherty KT, et al. SMR 2011. Abstract LBA1-4.

--80

--60

--40

--20

0

20

40

1.0 0.4 0 0.6 4.2 -- 0.3 2.1 4.3 2.6 7.7 0.5 0.2 1.0 -- 6.2 0.5 1.0 0.2 7.4 9.21.1 1.1

M

M M M

M

Supervivencia con inhibición BRAF/MEK en función de inhibidor BRAF previo

0 6 12 18 24 30 36 420

0.2

0.4

0.6

0.8

1.0

Mos From Randomization/First Dose

Prop

ortio

n A

live

Part C 150/2 (n = 54)Part B 150/2 BRAFi naive (n = 24)Part B 150/2 BRAFi failure (n = 26)

Flaherty KT, et al. ASCO 2014. Abstract 9010.

Retratamiento con BRAFi

Thakur MD and Stuart D D Cancer Res 2013

Los tumores resistentes a BRAFi muestran dependencia contínua de la señalización BRAF(V600E)→MEK→ERK debido a sobreexpresión BRAF(V600E)

La discontinuación del tratamiento conduce a la regresión de tumores resistentes

Thakur MD Nature 2013

Retratamiento con BRAFi

Tratamiento discontínuo con IK/inmunoterapia

Los inhibidores kinasa pueden rescatar S100 durante el curso del tratamiento

Reinhard Dummer at 2015 ASCO Annual Meeting

Tratamiento combinado BRAFi + MEKi

Bases para la combinación

1.Hauschild A., et al. Lancet 2012;380:358. Updated in J Clin Oncol 2013 (suppl); ab 9013.

2.Flaherty KT., et al. N Engl J Med 2012;367:1694-1703.3.Long GV., et al. N Engl J Med 2014;371(20):1877-1888.4.Robert C., et al. N Engl J Med 2015;372(4):320-330.5.Larkin J., et al. N Engl J Med 2014;371(20):1867-1876.

BRAFi (dabrafenib/Vemurafenib)

PFS HR 0.37/0.38 v DTIC1

Hyperproliferative skin AEs

MEKi (trametinib)PFS HR 0.45 v

chemotherapy2

pERK

Proliferation SurvivalInvasion

Metastasis

RAS

MEK

BRAFi + MEKi ph3 studiesdabrafenib + trametinib

vemurafenib + cobimetinib

Decreased hyperproliferative skin AE3,4,5

BRAFmutBRAF

40%

NRAS

CRAFBRAF

MEK

ERK



Metric: BRAF•Trametinib vs DTIC•RR 22%, mPFS 4.8m•HR OS/PFS: 0.54/0.45


COMBI-v:BRAF•D+T vs Vemurafenib

COMBI-v: Dabrafenib+Trametinib vs Vemurafenib en primera línea en melanoma BRAFV600E/K

BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal

• BRAF V600E/K mutation• Stages IIIC or IV cutaneous

melanoma• Treatment-naive in advanced

or metastatic• ECOG PS 0 or 1• No brain metastases, unless

– Treated– Stable > 12 weeks

Stratification• BRAF V600E vs V600K

mutation• LDH (> ULN vs ≤ ULN)

Vemurafenib (960 mg BID)

(n = 352)

Dabrafenib (150 mg BID) + trametinib (2 mg daily)

(n = 352)

Interim OS Analysis

(n = 202)

Final OS Analysis(n = 288)

N = 1,644 screened

n = 704

Primary endpoint: OSSecondary endpoints: progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), safety

Dabrafenib+Trametinib vs Vemurafenib en primera línea en melanoma BRAFV600E/K :OS

Median Follow-up: D + T = 11 months and Vem = 10 months

Análisis OS por subgrupos (ITT)

HRFavours D +

TFavours

Vem

3.0

2.5

2.0

1.5

1.0

0.5

0

Baseline LDH > ULN

(n = 232)

Baseline LDH ≤ ULN

(n = 471)

≥ 65 years (n = 166)

< 65 years (n = 538)

Female (n = 316)

Male (n = 388)

V600E (n = 629)

V600K (n = 68)

0.75

0.68

0.81

0.46

0.71

0.61

0.58

0.78

Dabrafenib+Trametinib vs Vemurafenib en primera línea en melanoma BRAFV600E/K :PFS

Dabrafenib+Trametinib vs Vemurafenib en primera línea en melanoma BRAFV600E/K : Respuesta

Best confirmed responseDabrafenib + trametinib

(n = 351)Vemurafenib

(n = 350)

Complete response, n (%) 47 (13) 27 (8)

Partial response, n (%) 179 (51) 153 (44)

Stable disease, n (%) 92 (26) 106 (30)

Progressive disease, n (%) 22 (6) 38 (11)

Not evaluable, n (%) 11 (3) 26 (7)

Response rate, n (%)(95% CI)

226 (64)(59.1–69.4)

180 (51)(46.1–56.2)

Difference in ORR, % (95% CI)

13 (5.7–20.2)

P-value < 0.001

DoR, months (95% CI) 13.8 (11.0–NR) 7.5 (7.3–9.3)

NRAS

CRAFBRAF

MEK

ERK





COMBI-d:BRAF•D+T vs Dabrafenib

COMBI-v:BRAF•D+T vs Vemurafenib•RR 64%, mPFS 11,4m•HR OS/PFS:0.69/0.56

COMBI-d: DiseñoN = 947 screened

Primary Endpoint: Investigator-assessed PFSSecondary Endpoints: OS, overall response rate (ORR), duration of response, safety

N = 423

• BRAF V600E/K• Unresectable stage IIIC/IV• Treatment naïve• ECOG PS 0/1• No brain mets, unless:

▪ Treated▪ Stable ≥ 12 weeks

Stratification• BRAF mut V600E v K• LDH (>ULN v ≤ ULN)

dabrafenib + trametinib150 mg BID + 2 mg QD

n = 211

dabrafenib + placebo150 mg BID + placebo QD

n = 212

Pre-planned interim OS[95 events]

Primary Analysis

(PFS)[213 events]

Aug 2013

Final Analysis

(OS)[222 deaths]

Jan 2015

Long GV, et al. Lancet epub 31 May 2015.

No crossover to combination allowedSite staff and patients remained blinded

COMBI-d: Supervivencia Libre de Progresión

Time (months)

Dabrafenib + PlaceboEvents: 162 (76%)Median PFS 8.8 mo (95% CI:5.9–9.3)

HR 0.67 (95% CI: 0.53, 0.84)P < 0.001

Prop

ortio

n Pr

ogre

ssio

n-fr

ee1.0

0.8

0.6

0.4

0.2

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

211 196 164 137 125 96 84 80 71 70 65 61 38 26 6 0 0 0

212 177 139 109 96 81 65 52 47 40 35 31 19 16 4 0 0 0

Dabrafenib + trametinibNumber at risk

Dabrafenib + placebo

Dabrafenib + TrametinibEvents: 139 (66%)Median PFS 11.0 mo (95% CI:8.0–13.9)


PFS y OS en pacientes con LDH aumentada

COMBI-d: Supervivencia

Time (months)

211 208 200 187 174 159 144 135 124 112 106 103 88 53 21 3 0 0

212 206 191 175 159 147 138 127 111 104 95 88 70 42 10 2 1 0

Dabrafenib + trametinibNumber at risk

Dabrafenib + placebo

Dabrafenib + TrametinibDied: 99 (47%)Med OS = 25·1 mo (95% CI:19.2-NR)

DabrafenibDied: 123 (58%)Median OS = 18.7 mo (95% CI:15.2–23.7)

HR 0.71 (95% CI: 0.55, 0.92)P = 0.011

2-yr OS 51%

2-yr OS 42%Prop

ortio

n A

live

1.0

0.8

0.6

0.4

0.2

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

1-yr OS = 74%

1-yr OS = 68%

Dabrafenib+Trametinib med follow up 20 mo (range 0-30 mo); Dabrafenib med follow up 16 mo (range 0-32 mo).


COMBI-d: Tratamiento tras la progresiónDabrafenib +

Placeboa

n = 212n (%)

Dabrafenib + Trametinibb

n = 211n (%)

Study treatment continued post progressionc 65 (31) 62 (29)

Subsequent anti-cancer therapyd 108 (51) 70 (33)

Ipilimumab 59 (28) 37 (18)

BRAF inhibitor (vemurafenib and/or dabrafenib)

29 (14) 18 (9)

Pembrolizumab or nivolumab 14 (7) 6 (3)

Chemotherapy regimens 66 (31) 45 (21)

Other 14 (7) 4 (2)a35 (17%) remained on study treatment at data cut.b64 (30%) remained on study treatment at data cut.cReceived study treatment for at least 15 days after disease progression.dStudy treatment is not included.


COMBI-d: OS por subgrupos

Hazard ratio and 95% confidence interval

Factor Number of patients

Favors Dabrafenib + trametinib

Favors Dabrafenib + placebo

0.71

0.79

0.65

0.76

0.73

0.70

0.74

0.72

0.62

0.84

0.59

0.0 0.5 1.0 1.5 2.0

All patients 423

Age: < 65 years 305

≥ 65 years 118

BRAF mutation: V600E 360

V600K 61

Stage: IIIc/M1a/M1b 142

M1c 280

LDH: ≤ ULN 273

> ULN 148

No disease sites ≤ 2 228

≥ 3 193


COMBI-d: RespuestaDabrafenib + Placebo

(n = 210a)n (%)

Dabrafenib + Trametinib (n = 210a)

n (%)P-valueb

Best response

CR 28 (13) 33 (16)

PR 84 (40) 111 (53)

SD 66 (31) 50 (24)

PD 19 (9) 13 (6)

NE 13 (6) 3 (1)

Response rate

CR+PR 112 (53) 144 (69) 0.001 95% CI (46.3, 60.2) (61.8, 74.8)

Duration of response

Progressed or died, n (%) 79 (70) 86 (60)

Median, months (95% CI)

10.6 (9.1–13.8)

12.9 (9.4–19.5)

aNumber of patients with measurable disease at baseline.bChi-square test was used to calculate the P-value for difference between response rates.


NRAS

CRAFBRAF

MEK

ERK

COMBI-d:BRAF•D+T vs Dabrafenib•RR 69%, mPFS 11 m•HR OS/PFS:0.71/0.67


coBRIM: BRAF•V+Cobimetinib vs Vemura





coBRIM

Primary end pointPFS, investigator assessed1

Secondary end pointsOS, objective response rate, duration of response, PFS, IRC assessed, safety, pharmacokinetics, quality of life: QLQ-C30 and EQ-5D

1:1®

•Melanoma, unresectable locally advanced or metastatic (n = 495)

•BRAFV600 mutation (cobas® 4800)

•No prior systemic therapy for advanced disease

•ECOG PS 0/1

Vemurafenib 960 mg BID × 28 days (Days 1-28) +

Cobimetinib 60 mg QD × 21 days (Days 1-21)

Vemurafenib 960 mg BID × 28 days (Days 1-28) +

Placebo

Disease progression, unacceptable

toxicity, or withdrawal of

consent

BID, two times daily; ECOG, Eastern Cooperative Oncology Group; EQ, EuroQol; HR, hazard ratio; IRC, independent review committee; OS, overall survival; PS, performance status; QD, once daily; QLQ, quality-of-life questionnaire.1. Larkin J et al. N Engl J Med. 2014;371:1867-1876.

Stratification•Geographic region•Extent of disease (M1c vs other)

Primary analysis for PFS: Performed in 2014 with the data cutoff as May 9, 2014. Protocol-specified first OS interim analysis was also performed1

Updated analysis for PFS: Presented here with the data cutoff as January 16, 2015.

coBRIM: Supervivencia libre de Progresión

ITT Population Cobi + Vemn = 247

Pbo + Vemn = 248

PFS events, n (%) 143 (57.9) 180 (72.6)

Median PFS, months(95% CI)

12.25b

(9.46-13.37) 7.20b

(5.55-7.49)

HRa (95% CI)

0.58b

(0.460-0.719)

aStratified HR. bThe median PFS was 6.2 months in Pbo + Vem, and 9.9 months in Cobi + Vem (HR, 0.51; 95% CI, 0.39-0.68) at the May 9, 2014 data cutoff.Larkin J et al. N Engl J Med. 2014;371:1867-1876.

100

80

60

40

20

0

Surv

ival

Dis

trib

utio

n Fu

nctio

n (%

)

Cobimetinib + vemurafenib (n=247)Placebo + vemurafenib (n=248)Censored+

No. of patients at riskVemurafenib + cobimetinibVemurafenib + placebo

238240

215205

190150

168115

14287

11667

7945

4630

2117

83

1

1 Months 5 Months 9 Months 13 Months 17 Months 21 Months 25 Months

Time

++

+

Kaplan-Meier Plot for PFSIntent-to-Treat Population

+++++

+

+++++++

++++++++++++++++++++

++++++++

+

+

+

+ +

+++

+

++

++

+++

+ +++

++++ ++ +++ +++++

+++++

Data cutoff of January 16, 2015 was 1 year from enrollment of last patient

Baseline Risk

FactorsTotal

n

Placebo + vemurafeni

b(n=248)

Cobimetinib + vemurafenib

(n=247)

nEvent

sMedian

(months) nEvent

sMedian

(Months)

Hazard

Ratio

95%Wald

CI

Disease Stage (IIIc/M1a/M1b, or M1c)

Age Group (yr)

Sex

Geographic Region

ECOG Performance Status

Screening Serum LDH

Prior Adjuvant Therapy

BRAFV600 Mutation Status

All Patients

495

248

180

7.2

247

143

12.3

0.59

(0.47, 0.73)

M1C

299

153

128

5.5

146

94

9.5

0.52

(0.40, 0.68)

Europe

366

138

6.0

182

107

11.2

0.58

(0.45, 0.75)

184

Unresectable Stage IIIC/M1A/M1B

196

52

11.0

101

49

13.4

0.73

(0.49, 1.08)

95

< 65

362

128

7.2

183

107

12.6

0.61

(0.47, 0.79)

179≥ 65 13

352

5.6

64

36

11.2

0.52

(0.34, 0.80)

69

Female

209

72

7.5

101

52

12.9

0.57

(0.40, 0.82)

108Mal

e286

108

5.7

146

91

11.1

0.58

(0.44, 0.77)

140

Australia/New Zealand/Others

78

26

7.4

40

20

13.3

0.57

(0.32, 1.03)

38

N. America

51

16

7.5

25

16

11.2

0.57

(0.28, 1.17)

26

0 348

110

7.6

184

100

12.9

0.65

(0.49, 0.85)

1641 13

866

5.5

58

41

10.0

0.53

(0.35, 0.78)

80

Elevated

216

85

5.4

112

78

8.2

0.57

(0.42, 0.78)

104Norma

l268

90

7.8

130

65

13.4

0.59

(0.43, 0.81)

138

Yes

48

16

7.2

24

12

16.5

0.60

(0.28, 1.27)

24No 44

7164

7.2

223

131

11.2

0.59

(0.47, 0.74)

224

V600E

344

126

7.2

170

102

10.6

0.64

(0.49, 0.83)

174V600

K56

32

24

6.0

24

14

12.4

0.52

(0.27, 1.02)

Cobimetinib + vemurafenib

better

Placebo + vemurafenib

better

1/100

1/10

1 10

100

PFS por subgrupos

coBRIM : Tasa de Respuestas

Cobimetinib + Vemurafenib

n = 247

Placebo + Vemurafenib

n = 248

Complete response (CR), n (%) 39 (15.8) 26 (10.5)

Partial response, n (%) 133 (53.8) 98 (39.5)

Objective response rate (ORR), n (%) 172 (69.6)(95% CI, 63.49-75.31)

124 (50.0)(95% CI, 43.61-56.39)

Difference in ORR, % 19.64a

(95% CI, 10.95-28.32)

Duration of response Patients with event, n (%) Median (95% CI) Range

84 (48.8)12.98 (11.10-16.62)

2.86-20.11

73 (58.9)9.23 (7.52-12.78)

1.77-17.68

aAt the primary analysis ORR was 68% and 45%, respectively, and CR was 10% and 4%, respectively. Larkin J et al. N Engl J Med. 2014;371:1867-1876.Data cutoff was January 16, 2015.

Supervivencia

Vemurafenib + Placebo

Vemurafenib + Cobimetinib

OS events, n 51 34Median OS NE NE

9-month OS (95% CI), % 72.5 (65.2-79.8)

81.1 (74.7-87.5)

HR (95% CI)P value two-sided

0.65 (0.42-1.00) P = 0.046*

Data Cutoff: May 9, 2014

Ove

rall

Surv

ival

, %

No. at Risk

243

245

229

227

182

166

112

101

62

53

20

21

6

2 1

1814 1610 126 82 4Time, months

Vemurafenib + cobimetinibVemurafenib + placebo

0

100

80

60

40

20

0

Vemurafenib + cobimetinib (n = 247)Vemurafenib + placebo (n = 248)Censored++

CI, confidence interval; NE, not estimable.* Descriptive p-value. Did not cross the pre-specified stopping boundary for the interim analysis (boundary p <0.0000037)

0

Update of Progression-Free Survival and Correlative Biomarker Analysis From coBRIM: Phase 3 Study of Cobimetinib Plus Vemurafenib in Advanced BRAF-

Mutated Melanoma

James Larkin, Yibing Yan, Grant McArthur, Paolo Ascierto, Gabriella Liszkay, Michele Maio, Mario Mandalà, Lev Demidov,

Daniil Stoyakovskiy, Luc Thomas, Luis de la Cruz-Merino,

Victoria Atkinson, Caroline Dutriaux, Claus Garbe, Matthew Wongchenko, Isabelle Rooney, Ilsung Chang,

Stephen P. Hack, Brigitte Dréno, Antoni Ribas

coBRIM Oncogenic Mutation ProfilingSequencing Targets

Gene Codon Range

HRAS 9-20, 59-76

KRAS 4-15, 55-65, 137-148

NRAS 9-20, 55-67

BRAF 581-615

EGFR 709-722, 737-749, 744-754, 757-761, 767-779, 788-798, 849-861

FGFR1 123-136, 250-262

FGFR3 363-374, 638-650

FLT3 829-840

KIT 557-579, 815-826

MET 1245-1256

PDGFRa 560-572, 840-853

RET 916-926

ABL1 249-258, 303-319

AKT1 16-27

AKT2 16-26

JAK2 607-618

PIK3CA 540-551, 1038-1049

RA

S/R

AF

RTK

Materiales

• DNA de tejido previo al tratamiento

Métodos

• Se analizaron mutaciones BRAF y 528 mutaciones conocidas activantes en 17 proteínas kinasas oncogénicas (Ion Torrent next generation sequencing)

• 423 muestras secuenciadas

• La mutación fue positiva cuando la frecuencia del alelo mutado fue detectada en >3% de las lecturas

• Los datos se correlacionaron con PFS y ORR

• En 46 de 423 muestras de pacientes (11%) se demostraron mutaciones coexistentes en RAS, RAF, y/o RTK

Distribution of Mutations in Assayed Oncogenes*60

50

40

30

20

10

0

Num

ber o

f Pat

ient

s

Coe

xist

ing

mut

atio

nR

AS

/RA

F/R

TKR

AS

/RA

FH

RA

SK

RA

SN

RA

SB

RA

F N

on-V

600

EG

FRFG

FR3

FLT3 KIT

PD

GFR

aJA

K2

PIK

3CA

RAS/RAF RTK*Includes patients with ≥1 coexisting mutation.

Baseline Oncogene Mutations Coexist With BRAFV600 Mutations in coBRIM Patients

#Allelic frequencies of co-existing oncogene mutations in baseline tumor tissues ranged from 5 – 99 % with median of 8.6%

Kaplan-Meier Plot of PFS for Sequenced Patients in Both Treatment Arms

Coexisting mutations were not associated with worse PFS in either treatment arm

pERK in Available Samples by RPPA1

RAS/RAF/RTK co-mutants have higher MAPK pathway activity, as measured by pERK

1RPPA, reverse-phase protein array.

RAS/RAF/RTK WT

RAS/RAF/RTK Mut

ORR 60% 61%

Coexisting Baseline RAS/RAF/RTK Mutations Were Not Associated With Worse PFS or ORR in coBRIM Patients

55

Greater Clinical Benefit Obtained in Advanced BRAFV600-mutated Melanoma with Cobimetinib/Vemurafenib Over

Vemurafenib Is Consistent Across Mutation Subtypes

ESMO 2015

Resumen eficacia BRAFi+MEKi

TR SLP SG %LDH elevado

Dabrafenib-Trametinib(Combi-d)

69% 11m 25,1m 36%

Dabrafenib-Trametinib(Combi-v)

64% 11,4m NA 34%

Vemurafenib-CobimetinibCo-BRIM

69,6% 12,25m NA 46%

Resumen Eventos Adversos

Vem Vem+Cobi Dabra Dabra+Trame

EA (total) 98% 98% 97% 97%EA >=G3 59% 65% 30% 32%EA que conducen a la discontinuación del tto

12% 13% 7% 11%


Larkin J et al. N Engl J Med. 2014;371:1867-1876

COMBI-d: Eventos Adversos en ≥20% de pacientes

Preferred TermDabrafenib + Placeboa

n = 211 n (%)

Dabrafenib + Trametinibb

n = 209n (%)

All Grades Grade 3 All Grades Grade 3

All Events 189 (90) 63 (30) 181 (87) 66 (32)Pyrexia 52 (25) 4 (2) 108 (52) 15 (7)Chills 29 (14) 1 (<1) 58 (28) 0Fatigue 59 (28) 2 (<1) 56 (27) 4 (2)Rash 42 (20) 1 (<1) 50 (24) 0Nausea 31 (15) 1 (<1) 41 (20) 0Arthralgia 49 (23) 0 34 (16) 1 (<1)Hyperkeratosis 70 (33) 1 (<1) 13 (6) 0Hand-foot syndromec 57 (27) 1 (<1) 13 (6) 1 (<1)

Alopecia 55 (26) 0 10 (5) 0aThree grade 4 events; 1 grade 5 event, treatment-related (bile duct adenocarcinoma).bOne grade 4 event; 5 fatal SAEs, not treatment related (3 intracranial hemorrhage,1 pneumonia,1 drowning).cCombined terms of palmar-plantar erythrodysesthesia and palmoplantar keratoderma. Long GV, et al. Lancet epub 31 May 2015.

HyperkeratosisPhotosensitivity reactionDermatologi

cAlopecia

Vomiting

Increased AST

Increased ALT

Pyrexia

Increased CPK

Fatigue

Arthralgia

Rash

NauseaDiarrhea

Other

Laboratory

GI

Percentage

Co-BRIM: Eventos Adversos en ≥20% de pacientes

Grade 1

Grade 2

Grade 3

Grade 4

Vemurafenib + Placebo (n = 239)

Vemurafenib + Cobimetinib (n = 254)

Data Cutoff: May 9, 2014Larkin J et al. N Engl J Med. 2014;371:1867-1876

EA relacionados con BRAFi o MEKi

Vemurafenib+Cobimetinib(%)

Dabrafenib + Trametinib

n (%)EA relacionados con BRAFi

cuSCC + KA 3+1 3EA relacionados con MEKi

Pirexia 9 52 (G3-4:7%)

Disminución Fracción eyección 7 4

Chorioretinopathyb 20 (G3-4 <3%) <1

Long GV, et al. Lancet epub 31 May 2015.Larkin J et al. N Engl J Med. 2014;371:1867-1876

NRAS

CRAFBRAF

MEK

ERK

COMBI-d:BRAF•D+T vs Dabrafenib•RR 69%, mPFS 11 m•HR OS/PFS:0.71/0.67


coBRIM: BRAF•V+Cobimetinib•RR 69,6%, mPFS 12,2m•HR OS/PFS: 0,65/0,58





Fase II NRAS•Binimetinib (MEK 162)•ORR 63%

Phase I/II Study: LEE011 + Binimetinib (MEK162) in NRAS-Mutant Melanoma

■ LEE011: oral selective CDK4/6 inhibitor■ Binimetinib: oral selective MEK1/2 inhibitor■ Phase Ib endpoints

■ Primary objective: determine the MTD and/or recommended phase II dose using a Bayesian logistic regression model with overdose control principle

■ Secondary objectives: safety and tolerability, PK, and clinical efficacy

Sosman JA, et al. ASCO 2014. Abstract 9009.

Metastatic or Locally Advanced NRAS-Mutant

Melanoma (N ≈ 40)

Phase II/Dose ExpansionPhase Ib/Dose Escalation

LEE011 + Binimetinib

Metastatic or Locally Advanced NRAS-Mutant

Melanoma •(N ≥ 15)

MTD and/orRP2D

*LEE011 for 21 consecutive days followed by a 7-day planned break and binimetinib on a continuous dosing schedule.

Cohort Binimetinib, mg BID

LEE011, mg QD

Patients, n

1 45 200 9

2 45 250 3

3 30 300 4

4 45 300 6

Phase Ib Doses and Schedule*

LEE011 + Binimetinib (MEK162) in NRAS-Mutant Melanoma: Responses

■ Several patients had early tumor shrinkage with major symptomatic improvementSosman JA, et al. ASCO 2014. Abstract 9009.

Response, n (%) LEE011 + Binimetinib

(N = 22)

CR 0

PRConfirmed PRUnconfirmed PR

7 (33)3 (14)4 (19)

SD 11 (52)*

20% to 30% tumor mass decrease by RECIST 1.1

7 (33)

Clinical benefit rate(CR + PR + SD)

18 (86)

PD 3 (14)

Unevaluable 1 (NA)

Overall Response Individual Patient Responses

*Includes 1 patient with KRAS-mutant pancreatic cancer.

-100

n = 21

* * * * * * * * * * **

-80

-60

-40

-20

0

20

40

60

80

100

Treatment Group

K

LEE 200 mg + MEK 45 mgLEE 250 mg + MEK 45 mg

LEE 300 mg + MEK 30 mgLEE 300 mg + MEK 45 mg

Best

Per

cent

age

Cha

nge

From

Bas

elin

e

*Ongoing as of April 14, 2014 K denotes patient with KRAS-mutant pancreatic cancer

Selumetinib (melanoma uveal)

R Carvajal et al JAMA. 2014 Jun 18; 311(23): 2397–2405.

Selumetinib Misses Endpoint in

Phase III Uveal Melanoma Study-

SUMMIT

http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=24938562

Conclusiones

■ Para el 50% de los pacientes con melanoma, la inhibición combinada BRAF y MEK mejora las respuestas y la SLP

■ Aumento en la supervivencia con medianas aún no alcanzadas y supervivencias prolongadas (51% a 2 años)

■ Tratamiento en primera línea, pendiente de establecer su papel en combinación/secuenciación con inmunoterapia

■ Es preciso mayor conocimiento de los mecanismos de resistencia y estrategias para revertirlos/retrasarlos

Documents

INHIBIDORES DE BRAF Y MEK DIRIGIDA CON TERAPIA · INHIBIDORES DE BRAF Y MEK ... Supervivencia con inhibición BRAF/MEK en función de inhibidor ... Los inhibidores kinasa pueden rescatar